Skin-Intrinsic Immunosuppressive Mesenchymal Stem Cells and aGVHD

皮肤固有免疫抑制间充质干细胞和 aGVHD

• 批准号: 10345441
• 负责人: NATASHA Y FRANK
• 金额: $ 43.35万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10345441
• 关键词: Acute Graft Versus Host Disease; Address; Affect; Allogeneic Bone Marrow Transplantation; Allogenic; Apoptosis; Attenuated; Biological Assay; Bone Marrow; Bone Marrow Cell Transplantation; Cell Communication; Cells; Cessation of life; Characteristics; Collaborations; Complement; Complication; Cutaneous; Cytokeratin; Cytokine Network Pathway; Data; Dendritic Cells; Dermal; Disease; Disease Progression; Epidermal Ridges; Epithelial; Epithelial Cells; Family member; Funding; Goals; Graft-Versus-Tumor Induction; Hair follicle structure; Home; Immune; Immune response; Immunophenotyping; Immunosuppression; Inflammatory; Laboratories; Lead; Life; Limb structure; Liver; Mediating; Mediator of activation protein; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Messenger RNA; Minor Histocompatibility Antigens; Modeling; Monitor; Morbidity - disease rate; Mucous Membrane; Multi-Drug Resistance; Mus; Organ; Organ Culture Techniques; Organ Transplantation; PD-1 pathway; PD-1/PD-L1; Pathology; Pathway interactions; Patients; Phenotype; Prevention; Proteins; RNA; Recovery; Research; Resistance; Resolution; Severity of illness; Site; Skin; Solid; Solid Neoplasm; Stem cell transplant; System; T cell response; T-Lymphocyte; TP53 gene; Therapeutic; Tissues; Validation; Work; Xenograft Model; base; cancer therapy; cytokine release syndrome; cytotoxic; design; digital; epithelial injury; epithelial stem cell; graft vs host disease; immune reconstitution; immunoregulation; in vivo; knockout gene; laser capture microdissection; leukemia treatment; leukemia/lymphoma; mouse model; novel therapeutic intervention; programmed cell death ligand 1; programmed cell death protein 1; skin disorder; spatiotemporal; stem cell biomarkers; stem cell engraftment; stem cell fate; stem cell function; stem cells; tissue injury

Project Summary/Abstract Acute graft-versus-host disease (aGVHD) is a major limiting complication of allogeneic stem cell transplantation for the treatment of leukemia/lymphoma and certain solid tumors. aGVHD occurs when T lymphocytes from donor bone marrow attack cells within the recipient that are critical to the function vital organs, namely skin, liver and gut. During the past three decades of research, Dr. Murphy’s laboratory has found that in skin and squamous mucosae, the first sites of effector-target cell interaction provoked by differences in minor histocompatibility antigens, involve T cells bearing Vb-specific markers that home selectively to epithelial rete ridges as well as the epithelial stem cell-rich bulge regions of murine hair follicles. This association results in death by apoptosis of adjacent epithelial cells that express the stem cell marker, cytokeratin 15. Systemic therapeutic inhibition of these effector limbs is riddled with problems that include collateral impact on immune reconstitution and blunting of graft-versus-tumor effects. However, we now know through discoveries made in collaboration with co-PIs of this proposal, Drs. Markus and Natasha Frank, that the skin and squamous mucosae harbor intrinsic cellular pathways capable of potent immunosuppression. Specifically, we have discovered a dermal dendritic cell that has stem cell characteristics, expresses the multidrug resistance transporter ABCB5, and also expresses PD-1. This cell has the ability to thwart T cell responses, including alloreactivity, and therefore holds significant but as yet unexplored promise as a skin- intrinsic pathway that may be leveraged to inhibit the tissue injury in aGVHD. In this proposal, Dr. Murphy and the Drs. Frank have combined forces to address the long-term objective of harnessing the skin’s intrinsic immunosuppressive capabilities to thwart aGVHD. The proposal’s specific objective is to determine the impact of PD-1-expressing immunosuppressive dermal mesenchymal stem cells on the earliest and most specific effector-target cell interactions responsible for aGVHD. To this end, we have proposed three specific aims: 1) to correlate spatiotemporal multiplex immune profiling with all aspects of disease morbidity and recovery in aGVHD; 2) to dissect ABCB5 dermal stem cell function in aGVHD and define PD-1/PD-L1-centered strategies for skin-intrinsic immunosuppression; and 3) to apply ABCB5+ dermal stem cell transplant strategies to influence aGVHD severity using spatiotemporal multiplex immune profiling as effector-target bioassay. The approaches involve state-of-the-art multiplex immunophenotyping of effector-target cell interactions that sensitively and specifically typify tissue injury in aGVHD, and leverage ABCB5 gene knockout and lineage tracing models in context of PD-L1 Ig administration and ABCB5+ stem cell engraftment. The rationale is that upon successful completion of this work, we will identify novel therapeutic approaches to the treatment and prevention of aGVHD skin and squamous mucosal pathology through manipulation of skin- intrinsic immunosuppressive pathways.

项目摘要/摘要 急性移植抗宿主病（AGVHD）是同种异体干细胞的主要限制并发症 治疗白血病/淋巴瘤和某些实体瘤的移植。当t时发生AGVHD 受体内供体骨髓攻击细胞的淋巴细胞对功能至关重要 器官，即皮肤，肝脏和肠道。在过去的三十年中，墨菲博士的实验室有 发现在皮肤和方形粘膜中，效应靶标细胞相互作用的第一个位置由 较小的组织相容性抗原的差异涉及带有VB特异性标记的T细胞 有选择地到上皮rete脊以及鼠毛囊的上皮干细胞隆起区域。 这种关联导致表达干细胞标记物的相邻上皮细胞的凋亡导致死亡 细胞角蛋白15。这些效应子四肢的全身治疗抑制，包括包括 对免疫重构和肿瘤肿瘤效应的侧支影响。但是，我们现在知道 通过与该提案的共同提议合作的发现，博士。马库斯和娜塔莎·弗兰克，那 皮肤和鳞状粘膜具有能够有效免疫抑制的内在细胞途径。 具体而言，我们发现了一个具有干细胞特征的皮肤树突状细胞，表达了 多药电阻转运蛋白ABCB5，还表示PD-1。该单元具有挫败T细胞的能力 反应，包括同种异体性，因此具有显着但出乎意料的承诺作为皮肤 - 可以利用以抑制AGVHD的组织损伤的固有途径。在此提案中，墨菲博士和 博士。弗兰克（Frank 免疫抑制能力阻止AGVHD。该提案的具体目标是确定影响 最早，最特异性的表达PD-1的免疫抑制皮肤间充质干细胞 负责AGVHD的效应靶标细胞相互作用。为此，我们提出了三个具体目标： 1）将时空多重免疫局与疾病发病率和恢复的各个方面相关联 在AGVHD中； 2）在AGVHD中剖析ABCB5皮肤干细胞功能并定义PD-1/PD-L1中心 皮肤免疫抑制的策略； 3）应用ABCB5+皮肤干细胞移植 使用时空多重免疫分析作为效应子目标，影响AGVHD严重程度的策略 生物测定。这些方法涉及效应靶标细胞的最新多重免疫表型 敏感和专门典型地典型地典型地典型的组织损伤的相互作用，并利用ABCB5基因基因敲除 PD-L1 IG给药和ABCB5+干细胞植入的背景下的谱系跟踪模型。这 理由是，成功完成这项工作后，我们将确定新颖的治疗方法 通过操纵皮肤来治疗和预防AGVHD皮肤和鳞状粘膜病理学 内在的免疫抑制途径。